Many patients with cervical spinal cord injury are dependent upon lifelong mechanical ventilatory support. While electrical stimulation techniques have been able to free some patients from mechanical ventilation, the vast majority still require their use. Given the significant disadvantages of these devices, additional pacing options are badly needed. We have recently demonstrated in preliminary animal testing that inspiratory muscle activation can be achieved with upper thoracic high frequency (>200 Hz) spinal cord stimulation (HF-SCS). This method entails stimulation of spinal cord tracts which synapse with the inspiratory motoneuron pools. This is a novel and more physiologic method of inspiratory muscle activation since stimulation occurs at a pre- motoneuron level, allowing for processing of the stimulus within the motoneuron pools resulting in a more physiologic recruitment pattern. This technique therefore has the potential to provide a more effective method of inspiratory muscle pacing. Prior to clinical trials, however, there are important aspects of this technique that require further characterization. The following objectives are designed to assess the biology of this technique by evaluating the optimal stimulus paradigm and electrode location, mechanism of HF-SCS, efficacy in terms of maintaining ventilation, optimal electrode design and, long term safety. In Objective I, optimal stimulus paradigm and electrode location resulting in activation of the inspiratory muscles will be determined by measurements of inspired volume and airway pressure generation. In Objective II, the mechanism of HF-SCS will be evaluated by inspiratory muscle EMG measurements including single motor unit recordings and measurements of rib cage and abdominal displacements. These results will allow us to test our hypothesis that HF-SCS results in a physiologic pattern of inspiratory muscle activation. Spinal cord ablation studies will be performed to determine the location of pathways mediating inspiratory motoneuron pool activation. In Objective III, electric field measurements will be used in conjunction with modeling techniques to determine optimal electrode designs. In Objective IV, the efficacy of HF-SCS in maintaining ventilatory support for prolonged time periods will be assessed. In Objective V, we plan to employ newly designed electrodes which will be used to assess the long term safety of this method in a chronic animal model. Stimulation will be provided for 18-24 hrs/day for 3 months. Following long term stimulation, pathologic examination of the spinal cord structures, spinal nerves and muscles will be undertaken. The results of these studies should resolve important basic science issues concerning this technique in animals, and provide the framework for human clinical trials. A more physiologic method of inspiratory muscle activation is likely to reduce the number of tetraplegics dependent upon mechanical ventilation and thereby improve their life quality. PUBLIC HEALTH RELEVANCE: Patients with paralysis secondary to cervical spinal cord injury are often dependent upon mechanical ventilators to support their breathing. These devices restrict mobility, are uncomfortable, interfere with the production of normal speech, provoke anxiety due to fear of disconnection and thereby reduce life quality. The proposed research will investigate new electrical stimulation methods to restore breathing and eliminate the disadvantages of mechanical ventilation.